SULF2 is an extracellular enzyme that removes 6-O-sulfate from heparan sulfate proteoglycans (HSPG). SULF2 is activated by convertases in the ER/Golgi compartments and, subsequently, secreted to stroma of tissues where it processes its HSPG substrates. Desulfation of HSPGs by SULF2 modulates multiple oncogenic signaling pathways and was associated with poor prognosis of several squamous cell carcinomas which express elevated amounts of the enzyme. SULF2 expression increases in several but was not examined in. In this study, we will examine expression of SULF2 in the epithelial surfaces of squamous cell carcinoma of the head & neck (HNSCC) because status of SULF2 remains undetermined in this malignancy. We will determine its localization, will study functional consequences of its activity, and will evaluate its presence in serum and saliva using newly optimized immunoaffinity reagents and mass spectrometric assays. This has important implication for early detection of HNSCC, evaluation of aggressiveness of the disease, and potential improvements of therapeutic interventions.